The selective eradication of neoplastic lesions, with minimal damage to normal host tissues, has been the goal of antitumor chemotherapy. Tumor photosensitization by a mixture of porphyrins derived from hematoporphyrin, and termed HPD (hematoporphyrin derivative), can display this degree of selectivity. This project is designed to elucidate the determinants of tumor localization by porphyrins and compounds of related structure. The long-term goal is the improvement of tumor-localization and phototherapy, e.g., by providing dyes which can be activated at wavelengths of light to which tissues are transparent, while minimizing the transient skin photosensitization which accompanies the current procedure. We have determined that the active components of HPD are dimeric and trimeric hematoporphyrin esters. Experimental evidence suggests that these HP esters bind to both plasma protein and lipoprotein, with subsequent distribution determined, in part, by the relative numbers of lipoprotein receptors in different tissues. Other esters of hematoporphyrin can be prepared using any porphyrin or analogous structure with a free carboxyl group. We plan to [1] incorporate into the ester molecule a moiety with other desirable characteristics, e.g., strong absorption in the near IR. [2] Examine the lipoprotein-receptor model as a determinant of tumor localization. [3] Explore fluorescence yields and photodynamic toxicity as a function of porphyrin structure. [4] Measure binding of porphyrins to tumor vs. skin, as a function of time and porphyrin structure. Porphyrins provided via a sub-contract at the University of California (Davis) will represent an approach to the directed design of new agents with a view toward the improvement of clinical phototherapy.